Nitro compounds of the formula A-Xi -NO2 and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities

ABSTRACT

PCT No. PCT/EP95/01233 Sec. 371 Date Mar. 6, 1997 Sec. 102(e) Date Mar. 6, 1997 PCT Filed Apr. 4, 1995 PCT Pub. No. WO95/30641 PCT Pub. Date Nov. 16, 1995New compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities, of the general formula: A-X1-NO2 or their salts, wherein: A is R(COXu)t, wherein t is zero or 1 and u is zero or 1; and X is O, NH or NR1C wherein R1C is C1-C10 alkyl; and R is(Ia) wherein R1 is acetoxoy, preferably n ortho-position with respect to -CO- and R2 is hydrogen; or derivatives of acetylsalylsalicyclic acid; and X1 is -YO- wherein Y is C1-C20 alkylene, C5-C7 cycloalkylene, oxy-alkyl derivatives and oxy-methyl benzyl derivatives.

The present invention relates to new products having anti-inflammatory,analgesic and anti-thrombotic activities.

In particular it relates to inhibitors of cyclo-oxygenase (COX).

It is known that the anti-inflammatory and anti-thrombotic efficacy, butmost of all the tolerance, of NSAIDs (Non Steroid Anti-InflammatoryDrugs), also known as FANS, seem to be considerably affected by theircyclo-oxygenase (COX)-inhibiting activity in the inflammatory site aswell as in healthy tissue. See for example FASEB Journal 1, 89, 1987;Bioch. Biophys. Acta 1083, 1, 1991. It is generally believed that themore potent a COX inhibitor is the more effective it is.

The disadvantage of these products is that they are toxic.

Furthermore, it is also known that the COX-inhibiting properties seem todepend on some factors related to the physico-chemical and structuralcharacteristics of the molecules themselves, such as for example theacidic function. See for example J. Pharmacol. Exp. Therap. 196, 226,1976; Arch. Toxicol. 60, 261, 1987.

The known cyclo-oxygenase inhibitors are generally acids which can bebrought back to general structures, including:

carboxyl acids, either acetylated such as, for example, aspirin andtriflusal, or nonacetylated such as, for example, salycilate,diflunisal, salsalate;

acetic acids, for example diclofenac, indomethacin, tolmetin, sulindac,etodolac, ketorolac;

propionic acids, such as, for instance, ibuprofen, naproxen, pirprofen,tiaprofenic acid, loxoprofen, indoprofen, oxaprozin, ketoprofen,fenoprofen, fenbufen, flurbiprofen, carprofen. suprofen;

enolic acids, such as, for example, oxyphenbutazone, phenylbutazone,piroxicam, sudoxicam, tenoxicam, isoxicam, meloxicam.

See patents U.S. Pat. No. 3,558,690; U.S. Pat. No. 3,755,427; U.S. Pat.No. 3,641,127; FR 2,112,111; U.S. Pat. No. 4,035,376; U.S. Pat. No.3,997,669; U.S. Pat. No. 3,784,701; U.S. Pat. No. 3,896,145; U.S. Pat.No. 3,600,437; U.S. Pat. No. 3,843,681; U.S. Pat. No. 3,904,682; U.S.Pat. No. 3,228,831; U.S. Pat. No. 4,161,538; U.S. Pat. No. 4,233,299;U.S. Pat. No. 3,591,584; DE 2,537,070; U.S. Pat. No. 3,161,654; U.S.Pat. No. 4,061,779; U.S. Pat. No. 4,556,672; U.S. Pat. No. 4,089,969.

The disadvantage of these products is that they are very effective buthighly toxic.

The importance of the acidic function lies in the fact that a masking ofthis function in COX inhibitors results in a virtually complete loss ofits prostanoid-inhibiting properties. See Drugs 35, 504, 1988.

Also known are products which are highly effective in inhibitingcyclooxygenase and have a low toxicity even though they do not containthe acidic function in their molecule.

These products are known as nitric esters with nonacidic ending. See forexample patents PCT WO 94/04484, which describes a particular group ofcompounds including the well known commercial product diclofenac; PCT/EP93/03193, which describes another specific group of compounds includingthe commercial products flurbiprofen and indoprofen.

The Applicant has unexpectedly found that other compounds having thetermination group --ONO₂, when X₁ =--YO--, as defined hereinafter, haveanti-inflammatory, analgesic and anti-thrombotic activities when used asmedicaments with high efficacy in cyclo-oxigenase inhibition and havelow toxicity.

A further object of the invention is that the known products as reportedin PCT WO 94/04484 and PCT/EP 93/03193 and the new compounds found bythe Applicant having X₁ =--YO-- have a pharmaco-dynamic disadvantage. Infact, in the biochemical test evaluating the cyclo-oxygenase-inhibitingactivity, experiments conducted by the applicant showed a high responsevariability, in the order of 10-40%.

This generally results in an erratic and unpredictable efficacy, so thatthe determination of a correct dosage is difficult.

In practice, higher doses must be administered to limit the abovevariability. The disadvantage lies in the risks of a higher incidence ofside effects.

Another disadvantage is that these products are difficult from aformulation point of view because oral or parenteral preparations aremore difficult to prepare than traditional preparations based on acidicFANS.

Molecule solubility is known be one of the most important propertiesaffecting the molecule pharmacokinetic and dynamic processes.

For example, for parenteral administration, particularly by theintravenous route, drugs must be formulated in soluble form.

Similarly, by the oral route, the solubilisation process is decisive forabsorption and interaction with the effector.

In this respect, the choice of particular solvents and/or excipients,including surfactants, etc., is also toxicologically critical. Forexample, an intravenous formulation should not cause haemolysis orincompatibility with blood constituents.

However, there is much evidence which indicates that surfactants andapolar solvents may be irritant. See, for instance, J. Pharm. Science72, 1014, 1983.

Trials conducted by the applicant using 0.1% Tween 80 and 1%dimethylsulphoxide to suspend nitroxybutylflurbiprofen showed that thissolvent was irritant to the gastric mucous membrane.

However, it was unpredictably found that, using a NO-flurbiprofenderivative as described below which is part of the object of the presentinvention, the amounts of Tween 80 and dimethylsulphoxide required forsuspension were lower, such that no irritant effects were caused, eventhough results were the same in terms of solubilisation.

It was unpredictably and surprisingly found after numerousinvestigations that it is possible to prepare anti-inflammatoryproducts, as described below, having a high cyclo-oxygenase-inhibitingactivity combined with low toxicity and pharmacokinetically satisfactoryresponses, and having a very limited response variability with anaverage variation coefficient of about one half that of known productspharmacodynamically, and easier to formulate as oral or parenteralpreparations.

This was totally surprising and unexpected as the factors which affectthe anti-inflammatory and anti-thrombotic efficacy of NSAIDs depend on anumber of parameters. Therefore, it is not possible to forecastpharmacokinetics, for example the product fraction absorbed, thepharmacodynamic activity, the toxicity and the COX-inhibiting propertiesand, most of all, no assumptions may be made to predict or limitresponse variability.

Object of the present invention are compounds, or their compositions, ofgeneral formula:

    A--X.sub.1 --NO.sub.2

or their salts, for use as medicaments, in particular asanti-inflammatory or antithrombotic agents, wherein:

A=R(COX_(u))_(t), wherein t is zero or 1; u is zero or 1, X=O, NH,NR_(1C) wherein R_(1C) is a linear or branched alkyl having 1 to 10 Catoms;

R is chosen from the following groups:

group I), wherein t=1 and u=1 ##STR1## wherein: R₁ is an OCOR₃ group,wherein R₃ is methyl, ethyl or a linear or branched C₃ -C₅ alkyl, or theresidue of a heterocycle with a single ring having 5 or 6 atoms whichmay be aromatic, partially or totally hydrogenated, containing one ormore heteroatoms independently chosen from O, N, and S;

R₂ is hydrogen, hydroxy, halogen, a linear or when permissible branchedalkyl having 1 to 4 C atoms, a linear or when permissible branchedalkoxyl having 1 to 4 C atoms, a linear or when permissible branchedperfluoroalkyl having 1 to 4 C atoms, for example trifluoromethyl,nitro, amino, mono- or di-(C₁₋₄) alkylamino;

R₁ and R₂ together are a dioxymethylene group, with the provisos thatwhen X=NH, then X₁ is ethylene and R₂ =H; R₁ cannot be OCOR₃ in position2 when R₃ is methyl; nI being 0 or 1.

Preferably, in Ia) X is equal to O or --NH, R₁ is acetoxy, preferably inortho-position, with respect to --CO--, X₁ is (CH₂ --CH₂ --O)₂, R₂ ishydrogen, most preferred are the following A--X₁ --NO₂ compounds:3-acetoxy-N-(2-nitroxyethyl)-benzamide,4-acetoxy-N-(2-nitroxyethyl)-benzamide,3-acetoxy-N-(5-nitroxypentyl)-benzamide;2-acetoxy-n-(5-nitroxypentyl)benzamide,N-2-(nitroxyethyl)-2-propionoxy-benzamide, 2-acetoxy-2-nitroxy-ethylbenzoate, 2-acetoxy-N-(cis-2-nitroxycyclohexyl)-benzamide,2-acetoxy-4-chloro-N-(2-nitroxyethyl)-benzamide,N-(2-nitroxyethyl)-2-((4-thiazolyldinyl)carbonyloxy)-benzamide hydrochloride, 2-nicotinoyloxy-N-(2-nitroxyethyl)-benzamide,2-acetoxy-5-nitroxypentylbenzoate;

preferably, in Ib) R₃ =CH₃, nI=0;

X is equal to O, X₁ is ethylene: in this case Ib) is the residue ofacetylsalicylsalicylic acid;

Compounds Ic) of the class Ic₁) 5-amino salicylic acid derivatives(5-amino-2-hydroxybenzoic acid) are known as mesalamine when the valenceis saturated with --COOH.

In compounds Ic₂) at least one of the --COOH is reacted to form thecompounds of the invention. When both --COOH are reacted one obtainsbifunctional compounds. When the compound is saturated with --COOH, isknown as olsalazine.

Compounds Ic₃) are known, when the starting radical has a --COOH assulfasalazine: 2-hydroxy-5- (4-(2-pyridinylamino)sulphonyl!phenyl!azo!benzoic acid.

The preferred compounds of Ic) have X=O and u=1 and X₁ is different from--YO--.

group II) wherein t=1, u=1 ##STR2## wherein: R_(II5) is H, a linear orbranched C₁ -C₃ alkyl when permissible R_(II6) has the same meaning asR_(II5), or, when R_(II5) is H, it may be benzyl;

R_(II1), R_(II2) and R_(III3) independently from one another arehydrogen, a linear or when permissible branched C₁ -C₆ alkyl, or C₁ -C₆alkoxy, or Cl, F, Br;

R_(II4) is R_(II1) or bromine;

preferred are the compounds wherein R_(II1), R_(II2) and R_(II4) are Hand R_(II3) is chlorine and R_(II3) is in the ortho position relative toNH;

R_(II5) and R_(II6) are H, X is equal to O, and X₁ is (CH₂ --CH₂ --O)₂ ;

IIb) is the residue of 2- (2-methyl-3-(trifluoromethyl)phenyl!amino!-3-pyridinecarboxylic acid! and when --COOH is present isknown as flunixin.

Preferred compounds are those in which u=1 and X=O.

group III), wherein t=1, u=1 and R is: ##STR3## wherein: R_(2a) andR_(3a) are H, a linear or when permissible branched, substituted ornon-substituted C₁ -C₁₂ alkyl, allyl, with the proviso that when one ofthe two groups is allyl, the other is H; preferably R_(2a) is H, analkyl having from 1 to 4 C, R_(3a) is H;

R_(1a) is chosen from ##STR4## III D) has the following compounds:##STR5## wherein the meanings are as follows: in the compound of formula(IV), residue of Ketoprofen:

R_(III1) is H, SR_(III3) wherein R_(III3) contains from 1 to 4 C atoms,linear or when permissible branched;

R_(III2) is H, hydroxy;

preferred are the compounds wherein R_(III1) and R_(III2) are H, R_(3a)is H and R_(2a) is methyl, X=O;

in the compounds of formula (XXI) residue of carprofen:

R_(XXio) is H, a linear or when permissible branched alkyl having from 1to 6 C atoms, a C₁ -C₆ alkoxycarbonyl bound to a C₁ -C₆ alkyl, a C₁ -C₆carboxylalkyl, a C₁ -C₆ alkanoyl, optionally substituted with halogens,benzyl or halobenzyl, benzoyl or halobenzoyl;

R_(XXi) is H, halogen, hydroxy, CN, a C₁ -C₆ alkyl optionally containingOH groups, a C₁ -C₆ alkoxy, acetyl, benzyloxy, SR_(XXi2) whereinR_(XXi2) is an alkyl C₁ -C₆ ; a perfluoroalkyl having from 1 to 3 Catoms, a C₁ -C₆ carboxyalkyl optionally containing OH groups, NO₂,ammino, sulphamoyl, a dialkyl sulphamoyl with the alkyl having from 1 to6 C atoms, or a difluoroalkylsulphonyl with the alkyl having from 1 to 3C atoms;

R_(XXi1) is halogen, CN, a C₁ -C₆ alkyl containing one or more OHgroups, a C₁ -C₆ alkoxy, acetyl, acetamide, benzyloxy, SR_(III3) asabove defined, a perfluoroalkyl having from 1 to 3 C, hydroxy, acarboxyalkyl having from 1 to 6 C, NO₂, ammino, a mono- or di-alkylaminohaving from 1 to 6 C, sulphamoyl, a di-alkyl sulphamoyl having from 1 to6 C, or a difluoroalkylsulphamoyl as above defined; or R_(XXi) togetherwith R_(XXi1) is an alkylene dioxy having from 1 to 6 C;

preferred are the compounds wherein R_(XXio) is H, the connecting bridgeis in position 2, R_(XXi) is H, R_(XXi1) is chlorine and is in the paraposition relative to nitrogen;

R_(3a) is H, R_(2a) is methyl and X is O;

in the compounds of formula (XXXV), residue of tiaprofenic acid:

Ar is phenyl, a hydroxyphenyl optionally mono- or poly-substituted withhalogen, an alkanoyl and an alkoxy having from 1 to 6 C, a trialalkylhaving from 1 to 6 C, preferably from 1 to 3 C, cyclo-pentyl,cylo-hexyl, cyclo-heptyl, heteroaryl, preferably thienyl, a furyloptionally containing OH, pyridyl;

the preferred (XXXV) compounds are those wherein Ar is phenyl, R_(3a) isH, R_(2a) is methyl and X is O;

in the compound of formula (II), residue of suprofen, of which the onepreferred has been shown, wherein R_(3a) is H, R_(2a) is methyl and X=O;its equivalents as described and obtained in U.S. Pat. No. 4,035,376,which is incorporated herein in full as a reference, may also be used;

in the compound of formula (VI),

of which the ones preferred indoprofen, when R_(2a) is CH₃ and indobufenwhen R_(2a) is equal to H, R_(3a) =--CH₃ and X=O have been shown;

its equivalents as described in and obtained in accordance with U.S.Pat. No. 3,997,669, which is incorporated herein in full as reference,may also be used;

in the compounds of formula (VIII),

of which the one preferred, etodolac, wherein R_(2a) =R_(3a) =H and X=Ohas been shown; its equivalents as described in and obtained inaccordance with U.S. Pat. No. 3,843,681, which is incorporated herein infull as reference, may also be used;

in the compounds of formula (VII),

of which the one preferred, fenoprofen, wherein R_(3a) =X, R_(2a) =--CH₃and X=O has been shown; its equivalents as described in and obtained inaccordance with U.S. Pat. No. 3,600,437, which is incorporated herein infull as reference, may also be used;

in the compounds of formula (III),

of which the preferred, fenbufen, wherein R_(2a) =R_(3a) =H and X=O hasbeen shown; its equivalents as described in and obtained in accordancewith patent U.S. Pat. No. 3,784,701, which is incorporated herein infull as a reference, may also be used;

in the compounds of formula (IX), residue of flurbiprofen wherein R_(3a)is H, R_(2a) is --CH₃ and X=O;

in the compounds of formula (X), residue of tolmetin, wherein R_(2a)=R_(3a) =H and X=O;

its equivalents as described in and obtained in accordance with patentFR 1,574,570, which is incorporated herein in full as a reference, mayalso be used;

In class III D) the meaning is the following:

IIIa) when it contains the --CH(CH₃)--COOH is known as pranoprofen:α-methyl-5H- 1!benzopyrano 2,3-b!pyridine-7-acetic acid.

In the preferred compound R_(2a) =H, R_(3a) =CH₃, u=1 and X=O.

The residue (XXX) when contains --CH(CH₃)--COOH is known as bermoprofen:dibenz b, f!oxepin-2-acetic acid.

The preferred compound has u=1, X=O, R_(2a) =H, R_(3a) =CH₃.

The residue of (XXXI) is known as CS-670: 2-4-(2-oxo-1-cyclohexylidenemethyl)phenyl!propionic acid, when the radicalis --CH(CH₃)--COOH.

The preferred compound has R_(2a) =H, R_(3a) =CH₃, u=1, X=O.

The residue (XXXII) derives from the known pemedolac which contains the--CH₂ COOH groups.

The preferred compound has R_(2a) =R_(3a) =H, u=1 and X=O.

This residue (XXXIII) is known as pirazolac when is saturated with --CH₂COOH:

4-(4-chlorphenyl)-1-(4-fluorphenyl)3-pyrazolyl acid derivatives.

Preferred compounds have R_(2a) =R_(3a) =H, u=1 and X=O.

The residue (XXXVI) when saturated with --CH(CH₃)--COO--, is known aszaltoprofen.

When the residue is saturated with an hydroxy or an amino group or thesalts of the acid, the compounds are known as dibenzothiepinderivatives.

The preferred products have a R_(2a) =H, R_(3a) =CH₃, u=1, X=O.

The residue (XXXVII) is deriving from the known mofezolac:3,4-di(p-methoxyphenyl)isoxazol-5-acetic acid when the residue is --CH₂--COOH.

Preferred compounds R_(2a) =R_(3a) =H, t=1, X=O.

group IV) in which t=1, u=1 and R is ##STR6## wherein: R_(IVd) andR_(IVd1) are at least one H and the other a linear or when permissiblebranched C₁ -C₆ alkyl, preferably C₁ and C₂, or a difluoroalkyl with thealkyl having from 1 to 6 C, C₁ is preferred, or R_(IVd) and R_(IVd1)together form a methylene group;

R_(IV) has the following meaning: ##STR7## wherein the compounds ofgroup IV) have the following meanings: in the compounds of formula (II):

R_(iv-ii) a 1-6 C alkyl, a cycloalkyl having from 3 to 7 C, analkoxymethyl having from 1 to 7 C, a trifluoroalkyl having from 1 to 3C, vinyl, ethinyl, halogen, an alkoxy having from 1 to 6 C, adifluoroalkoxy with the alkyl having from 1 to 7 C, an alkoxymethyloxyhaving from 1 to 7 C, an alkylthiomethyloxy with the alkyl having from 1to 7 C, an alkyl methylthio with the alkyl having from 1 to 7 C, cyano,difluoromethylthio, phenyl-or phenylalkyl substituted with the alkylhaving from 1 to 8 C;

preferably R_(iv-ii) is --CH₃ O, R_(IVd) is H and R_(IVd1) is --CH₃, andis known as a residue of naproxen;

X=NH and X₁ is equal to --(CH₂ --CH₂ --O)₂ ; also preferred is the samecompound wherein X is equal to O;

in the compounds of formula (X),

of which the residue of loxoprofen has been shown, the residuesdescribed in U.S. Pat. No. 4,161,538, which is incorporated herein infull as a reference, may be used as equivalents. Preferred are thecompounds in which R_(IVd) is H and R_(IVD1) is CH₃, X=NH and X₁ isequal to (CH₂ --CH₂ --O)₂ ; also preferred is the same compound whereinX is equal to O;

in the compounds of formula (III):

R_(iv-iii) is a C₂ -C₅ alkyl, even branched whenever possible, a C₂ andC₃ alkyloxy, allyloxy, phenoxy, phenylthio, a cycloalkyl having from 5to 7 C atoms, optionally substitutes in position 1 by a C₁ -C₂ alkyl;

preferred is the compound wherein R_(iv-iii) is ##STR8## and R_(IVd) =H,R_(IVd1) is --CH₃, a compound known as a residue of ibuprofen;

X=NH and X₁ is equal to (CH₂ --CH₂ --O)₂ ; also preferred is the samecompound wherein X is equal to O;

group V) ##STR9## In group V), the compounds have the followingmeanings: in the compounds of formula (II)

R_(vii) is H or a linear or when permissible branched alkyl having from1 to 4 C;

R_(vii-1) is R_(vii) or a linear or when permissible branched alkoxyhaving from 1 to 4 C; Cl, F, Br; the position of R_(vii-1) being o-,m-or p-;

preferred is the residue of the known ketorolac, wherein R_(vii) andR_(vii-1) are H, and A=R and t=0

in the compounds of formula (V),

of which the residue of the known tenidap has been shown, itsequivalents as described and obtained in U.S. Pat. No. 4,556,672, whichis incorporated herein in full as a reference, may also be used;

in these compounds of formula (V) A=R and t=0,

in the compounds of formula (VII)

of which the residue of the known tenoxicam has been shown, A is RCO andt=1 and u=0 or A is R and t=0; its equivalents as described and obtainedin patent DE 2,537,070, which is incorporated herein in full as areference, may also be used;

in the compounds of formula (IX)

where A=R and t=0, or A=RCO with t=1 and u=0, of which the residue ofthe known piroxicam has been shown, its equivalents as described andobtained in U.S. Pat. No. 3,591,584, which is incorporated herein infull as a reference, may also be used;

in the compounds of formula (III)

where A=RCOO, t=1 and u=0 or 1; or t=0 and A=R, of which the residue ofthe known nabumetone has been shown, its equivalents as described andobtained in U.S. Pat. No. 4,061,779, which is incorporated herein infull as reference, may also be used;

in the compounds of formula (IV)

where A=RCOO, t=1, u=1 of which the residue of the known indomethacinhas been shown, its equivalents as described and obtained in U.S. Pat.No. 3,161,654, which is incorporated herein in full as reference, mayalso be used.

in compounds of formula (X):

the residue (X) is known as meloxicam.

Preferred compounds are those in which t=0.

The residue (XI) is known as ampiroxicam when the termination is --COOC₂H₅.

The preferred compounds have u=1 and X=O; or t=0.

The residue (XII) when is saturated with --CH₂ COO-- is known asbromfenac.

The preferred compounds have u=1, X=O and R_(2a) =R₃ a=H; or t=0.

The residue XIII) derives from the known Lornoxicam when the valence issaturated with H.

Preferred compounds have t=0.

X₁ in the formula A--X₁ --NO₂ is a bivalent connecting bridge chosenfrom the following:

--YO--

where Y is:

a linear or when permissible branched C₁ -C₂₀ alkylene, preferablyhaving from 2 to 5 carbon atoms, excluding this connecting bridge when Ris:

a radical of group I) except class Ib) and Ic);

a radical of group II) except II_(b));

a radical of group III) except class of compounds of IIID)

a radical of group IV);

a radical of group V), except X) and including --(CH₂)₄ -- for thecompounds of formulae (III) and (IV);

or a cycloalkylene having from 5 to 7 carbon atoms optionallysubstituted; ##STR10## wherein n₃ is 0 or an integer from 1 to 3##STR11## wherein nf' is an integer from 1 to 6, preferably from 1 to 3;##STR12## wherein R_(1f) =H, --CH₃ and nf is an integer from 1 to 6,preferably from 2 to 4.

The compounds containing R of group I of type Ia) are described inpatent WO92/01668 wherein the preparation methods are also described.This patent is incorporated herein in full as a reference. The compoundsof type Ib) are prepared, for instance, using the method described inthe Merck Index, XI Ed., 1989, page 16, n.95, for the residue ofacetylsalicylsalicylic acid. The changes in the compounds of formula Ib)may be obtained applying the processes described in patent WO 92/01668.

Compounds Ic) of the class Ic₁), in which the radical is a 5-aminosalicylic acid derivative (5-amino-2-hydroxybenzoic acid) known asmesalamine, when the starting radical contains --COOH, are prepared byreduction of m-nitrobenzoic acid with Zn dust and HCl (see H. Weil etal., Ber. 55B, 2664 (1922)); or by electrolitic reduction: Le Guyader,Peltier, Compt. Rend. 253, 2544 (1961). These publications areincorporated here by reference.

The starting radical Ic₂) when it contains --COOH is known asolsalazine: 3,3'-azobis(6-hydroxybenzoic acid); and it is preparedaccording to EP 36,636 or U.S. Pat. No. 4,528,367, here bothincorporated by reference.

Compounds Ic₃) are prepared according to U.S. Pat. No. 2,396,145 hereincorporated by reference.

Equivalent compounds to Ic₁), Ic₂) and Ic₃) contain the substituentsindicated in the above references.

The products of the present invention having the general formula

    A--X.sub.1 --NO.sub.2

with the connecting bridges X₁ as above defined, with respect to thecompounds of group I), may be obtained using the above methods of theknown art or changing the known methods by introducing bridges X₁ whenthese are different from the connecting bridges described in the abovepatents.

The compounds wherein R is of group II) are described in patentsWO94/04484 and U.S. Pat. No. 3,558,690 wherein the preparation methodsare also described. These patents are incorporated herein in full as areference.

The starting compound of IIb), when the valence is saturated with --COOH(flunixin), is obtained according to U.S. Pat. No. 3,337,570 and U.S.Pat. No. 3,689,653 here incorporated by reference. Compounds containingthe substituents indicated in the above patents are equivalent toflunixin.

With respect to the compounds of group II), the connective bridges X₁ asabove defined may be obtained using the above methods of the known artor changing the known methods by introducing bridges X₁ when these aredifferent from the connecting bridges described in the above patents.

The compounds wherein R is of group III) are described and obtained bythe processes explained in the following patents: patent applicationPCT/EP/93 03193; for the compounds of formula (IV) also see U.S. Pat.No. 3,641,127; for the compounds of formula (XXI) also see U.S. Pat. No.3,896,145; for the compounds of formula (IX), residue of flurbiprofen,also see U.S. Pat. No. 3,755,427; for the compounds of formula (II) alsosee U.S. Pat. No. 4,035,376; for the compounds of formula (VI) also seeU.S. Pat. No. 3,997,669; for the compounds of formula (VIII) also seeU.S. Pat. No. 3,843,681; for the compounds of formula (VII) also seeU.S. Pat. No. 3,600,437; for the compounds of formula (III) also seeU.S. Pat. No. 3,784,701. All these patents are incorporated herein infull as a reference.

The processes for the preparation of compounds of class III D) are thefollowing:

IIIa) residue is obtained by preparing the acid compound, according toU.S. Pat. No. 3,931,205, the valence is saturated with --CH(CH₃)--COOH.Compounds containing the substituents indicated in the above patent areequivalent to pranoprofen.

The residue (XXX) is prepared through the compound with --CH(CH₃)--COOH(bermoprofen) according to U.S. Pat. No. 4,238,620 here incorporated byreference. Other equivalent products are listed in the above patent.

The residue (XXXI) is prepared by starting from the corresponding acid--CH(CH₃)--COOH, according to U.S. Pat. No. 4,254,274. Equivalentcompounds are listed in that patent.

The residue (XXXII) is prepared according to EP 238226 here incorporatedby reference when the valence is saturated with --CH₂ COOH. Equivalentproducts are reported in said patent as substituted 1,3,4,9tetrahydropyrane 3,4-b! indole-1-acetic acids.

The residue (XXXIII) is prepared by pirazolac (the valence is saturatedwith --CH₂ COOH), as indicated in EP 54,812 here incorporated byreference. Equivalent products are listed in the said patent.

The residue (XXXVI) is prepared according to the patent UK 2,035,311here incorporated by reference, by starting from zaltoprofen havingtermination --CH(CH₃)--COO--. Equivalent products are listed in the saidpatent.

The process of preparation of the residue XXXVII) is obtained bystarting from the Mofezolac and it is prepared according to EP 26928.Equivalent products are reported therein.

With respect to the compounds of group III), the connecting bridges X₁as above defined may be obtained using the above methods of the knownart or changing the known methods by introducing bridges X₁ when theseare different from the connecting bridges described in the abovepatents.

The compounds wherein R is of group IV) are described in WO-95-09831wherein the preparation methods are also described. This patent isincorporated herein in full as a reference.

In group IV) the compounds may also be obtained: for the compounds offormula (II), using patent U.S. Pat. No. 3,904,682; for the compounds offormula (X), in accordance with patent U.S. Pat. No. 4,161,538; for thecompunds of formula (III), in accordance with patent U.S. Pat. No.3,228,831. These patents are fully included in the present applicationas a reference.

With respect to the compounds of group IV), the connecting bridges X₁ asabove defined may be obtained using the above methods of the known artor changing the known methods by introducing bridges X₁ when these aredifferent from the connecting bridges described in the above patents.

The compounds wherein R is of group V) are described in the Italianpatent MI94A 000916 wherein the methods of preparation are alsodescribed. This patent is incorporated herein in full as a reference. Ingroup V) the compounds may also be obtained: for the compounds offormula (II), using patent U.S. Pat. No. 4,089,969 which is incorporatedherein in full as a reference; for the compounds of formula (V) may beobtained in accordance with patent U.S. Pat. No. 4,556,672 which isincorporated herein in full as a reference.

The residue (X) is prepared according to German patent 2,756,113.Equivalent products are listed in the said patent.

The residue (XI) is prepared according to the patent EP 147,177 hereincorporated by reference, by starting from ampiroxicam having thetermination --COOC₂ H₅. Equivalent products are listed in the saidpatent.

The residue (XII) is prepared according to J. Medicinal Chem., vol. 27,No. 11, November 1984, Walsh et al, Antiinflammatory Agents. 3.Synthesis and Pharmacological Evaluation of2-Amino-3-Benzoylphenylacetic Acid and Analogues, here incorporated byreference. Equivalent products are listed in said publication.

The residue (XIII) is prepared by starting by the Lornoxicam, whereinthe valence is saturated with H. It is prepared according to GBP2,003,877. Equivalent products are described in said patent.

With respect to the compounds of group V), the connecting bridges X₁ asabove defined may be obtained using the above methods of the known artor changing the known methods by introducing bridges, X₁ when these aredifferent from the connecting bridges described in the above patents.

Generally, the connection between A and X₁ is, as we saw, generally, ofthe ester or amide type (NH or NR_(1C), as defined in X) when R is ofgroups I), II), III), IV). All well known synthetic routes for formingthese bonds may be used to form this connection.

In the case of esters of group I), III) and IV), the most directsynthetic route involves a reaction of acyl chlorides R--CO--Cl withhalogen alcohols of the HO--Y--Cl, HO--Y--Br, HO--Y--I types, in theexperimental conditions of the known art.

The reaction products of formula R--CO--O--Y--Cl(Br,I) may also beobtained for class II by reacting the sodium or potassium salts of saidR--CO--OH acids with dihalogen derivatives of the general formula YCl₂,YBr₂ or YI₂.

The reaction products are converted into the final products by reactingwith AgNO₃ in acetonitrile, in accordance with literature reports.

The general route for groups I), III), IV) is as follows:

    R--CO--Cl+HO--Y--Br→R--CO--O--Y--Br+AgNO.sub.3 →A--X.sub.1 --NO.sub.2

wherein X₁ =YO.

The general route for group II is as follows:

    R--CO--ONa+Br.sub.2 Y→R--CO--O--Y--Br+AgNO.sub.3 →A--X.sub.1 --NO.sub.2

wherein X₁ =YO.

In the case of amides the synthetic route involves a reaction of thesame acyl chlorides RCOCl with amino alcohols of the general formula NH₂--Y--OH, NHR_(1C) --Y--OH to give amides of the general formula:

    R--CO--NH--Y--OH and R--CO--NR.sub.1C --Y--OH

in accordance with known methods.

The reaction of said amides with halogenating agents such as, forexample, PCl₅, PBr₃, SOCl₂, etc., leads to halogen derivatives of thegeneral formula:

    R--CO--NH--Y--Br(Cl) and R--CO--NR.sub.1C --Y--Br(Cl).

These, by reacting with AgNO₃ in acetonitrile in accordance with knownliterature methods, lead to the final products A--X₁ --NO₂.

The route may be outlined as follows:

    PCl.sub.5

    R--CO--Cl+NHR.sub.1C --Y--OH→R--CO--NR.sub.1C --Y--OH→R--CO--NR.sub.1C --Y--Cl+AgNO.sub.3 →R--CO--NR.sub.1C --Y--ONO.sub.2

wherein YO is X_(X1).

An alternative route to form the esters is a reaction of the sodium orpotassium salts of the acids with the nitric esters of halogen alcoholsof the general formula:

    NO.sub.2 --O--Y--Cl (Br,I)

to directly give the products of the invention.

The reaction route is as follows:

    R--CO--ONa+Br--Y--ONO.sub.2 →R--CO--O--Y--ONO.sub.2

wherein YO is X₁.

Synthetic routes similar to those described above can be used forproducts Va and Vb of group V), wherein the dihalogen derivative Br₂ Yis reached with enolates, for example, of tenoxicam or piroxicam. Thereaction products are then converted, in acetonitrile, by reacting withAgNO₃ in accordance with the above reaction.

The general route shown below relates to the piroxicam of formula IX ingroup V). ##STR13##

The above indicated products in the various groups are used asanti-inflammatory, analgesic, and anti-thrombotic activities. For groupI) no exclusion in the meanings of X₁ is necessary.

For groups II), III), IV) and V), the meaning of X₁ is limited as aboveindicated for these uses, when X₁ =--YO-- for some compounds.

A further object of the invention is that it was surprisingly found thatthe products of the invention containing --ONO₂ groups are capable ofhaving an effect inhibiting the inflammation induced by liposaccharide(LPS), and can, therefore, be used in septic shock.

This was surprising since it is well known that, generally,anti-inflammatories do not significantly change the nitrosynthetaseactitivity induced by lipopolysaccharides in rats and, therefore, cannotbe used in septic shock.

The products which may be used for this pharmaceutical use are theproducts of the general formula

    A--X.sub.1 --NO.sub.2

described above, wherein the bivalent connecting bridge X₁ has nolimitation in this case, i.e. the known connecting bridges are notexcluded as nothing was described in previous patents for this use.

It must be understood that when the compounds of the various groupscontain at least one asymmetric carbon, the products can be used inracemic form or as single isomers. It is in fact well known that in thetherapeutic uses of the invention in general an isomeric form is moreactive than the others.

The following examples are being given as an explanation not alimitation of the present invention.

EXAMPLES Example 1 Chemical Examples--Product Preparation

Example 1a:

Preparation of compound A--X₁ --NO₂, wherein R belongs to class I, X₁ is--(CH₂ --CH₂ --O)₂ --, herein referred to as ASA.NO-DEG, and having thegeneral formula:

2-acetoxy-benzoate of 2- 2-(nitroxy)ethoxy!ethyl ##STR14## Preparationof the intermediate of the formula: 2-acetoxy-benzoate of 2-2-(chloro)ethoxy!ethyl ##STR15##

1.0 g of sodium hydride (NaH) (80% suspension in white mineral oil) wasadded portionwise to a solution of:

acetylsalicylic acid 5.6 g and

dimethylformamide 20 ml

kept at 0° C. in a stream of nitrogen.

The mixture was stirred for one hour and then added dropwise over 5hours to a stirred solution of

2,2'-dibromo-diethylether 10.0 g and

dimethylformamide 15 ml

at 25° C. The mixture was stirred continuously for 3 days, then dried atreduced pressure. The residue was treated with:

water 50 ml and

dichloromethane 50 ml.

The phases were separated and the aqueous phase was extracted furtherwith dichloromethane 10 ml.

The pooled organic phases were washed with water (3×25 ml), dried(MgSO₄), decoloured with animal charcoal (1 g), and brought to drynessin vacuum.

The residue (11.2 g) was used crude for the next reaction.

Preparation of ASA-NO-DEG:

8.6 g of silver nitrate were added to a solution of

ASA--(CH₂)₂ --O--(CH₂)₂ Cl 11.2 g and

acetonitrile 25 ml

kept at ambient temperature and sheltered from light.

After stirring for two days, 2.2 g of silver nitrate were added.

After another two days in the same conditions, the insoluble salts werefiltered and the filtrate was freed of the solvent at reduced pressure.

A residue of 7.0 g was obtained and chromatographed on a silica gelcolumn (500 g of silica) eluting with a toluol/ethyl acetate 95/5 v/vmixture.

The fractions which were found to be uniform by TLC (Thin LayerChromatography) were pooled and brought to dryness. They yielded 3.0 gof ASA-NO-DEG.

A ¹ H NMR analysis (CDCl₃) (80 MHz) provided the following data:2.28(3H,s); 3.7(4H,m); 4.35(2H, t); 4.52(2H,t); 7.3 (3H,m); 7.98(1H,dd).

The IR analysis (nujol) provided the following results. ν_(OCO) =1780cm⁻¹ ; ν_(COO) =1725 cm⁻¹ ; ν_(ONO2) =1641 e 1287 cm⁻¹.

Mass spectrometry gave a molecular weight value of 313.

Example 1b:

Preparation of compound A--X₁ --NO₂, wherein R belongs to class II), X₁is --(CH₂ --CH₂ --O)₂ --, herein referred to as DICLOFENAC-NO-DEG, andhaving formula:

2-{N- 2,6-(dichloro)phenyl!amino}phenylacetate of 2-2-(nitroxy)ethoxy!ethyl ##STR16## Preparation of the intermediate havingformula 2-{N- 2,6-(dichloro)phenyl!amino}phenylacetate of 2-2-(bromo)ethoxy!ethyl ##STR17##

A solution of

DICLOFENAC sodium salt 13.3 g and

dimethylformamide 25 ml

was added to a solution of

2,2'-dibromo-diethylether 12.3 g and

dimethylformamide 15 ml

kept at ambient temperature in a stream of nitrogen.

The mixture was allowed to react for two days, and the solvent was thenremoved at reduced pressure. The residue was treated with ethyl acetate(50 ml), washed with a 5% solution of potassium carbonate (2×10 ml),then with water (20 ml), dried over anhydrous sodium sulphate. Thesolvent was removed at reduced pressure.

The residue weight was 16 g and was used for the next reaction with nopurification.

Preparation of DICLOFENAC-NO-DEG:

Silver nitrate 8 g in

acetonitrile 16 ml

were added to a solution of

DICLOFENAC --(CH₂)₂ --O--(CH₂)₂ --Br 16 g and

acetonitrile 30 ml

kept at room temperature and sheltered from light.

The mixture was stirred at ambient temperature for 3 days.

Silver nitrate 3 g after 1 day

silver nitrate 3 g after 2 days

were then added.

The mixture was stirred for another 2 days. The insoluble salts werethen filtered and the solvent removed from the filtrate at reducedpressure. The residue was treated with ethyl acetate (50 ml), theinsoluble salts were then filtered and discarded. The solvent wasremoved from the filtrate at reduced pressure. A residue of 16.2 g wasobtained and chromatographed on a silica gel column (700 g of silica)eluting first with toluol, then with a toluol/ethyl acetate 99/1 v/vmixture, finally with a toluol/ethyl acetate 98/2 v/v mixture.

The fractions found to be uniform by TLC analysis (thin layerchromatography) were pooled and brought to dryness to yield 4.38 g ofDICLOFENAC-NO-DEG.

A ¹ H-NMR analysis (CDCl₃) (300 MHz) provided the following data: 3.69(4H,t); 3.87 (2H,s); 4.3 (2H,m); 4.52 (2H,t) 6.55 (1H,d); 6.88 (1H, wides exchanged for D₂ O, NH); 6.97 (2H,t); 7.11 (2H,d); 7.23 (2H,d); 7.35(2H, d).

Mass spectrometry yielded a molecular weight value of 588.

Example 1c:

Preparation of compound A--X₁ --NO₂, wherein R belongs to class III) andrepresents the residue of the compound of formula IV, X₁ is --C₆ H₅ CH₂--, herein referred to as KETOPROFEN-NO-DEG, and having formula:

2-(3-benzoyl)phenylpropionate of 3-(nitroxymethyl)phenyl ##STR18##Preparation of intermediate 3-nitroxymethyl-phenol having formula:##STR19##

The reagents below are used in the amounts indicated and reacted asdescribed below:

3-hydroxy-benzylalcohol 10 g

48% HBr by weight 50 ml

CH₂ Cl₂ 30 ml

AgNO₃ 13.7 g

CH₃ CN 70 ml

3-Hydroxy-benzylalcohol in CH₂ Cl₂ was reacted with HBr at ambienttemperature for 4 hours.

CH₂ Cl₂ was then evaporated at reduced pressure at 30° C. after washingwith an aqueous 5% NaHCO₃ solution and drying over anhydrous Na₂ SO₄.

The oily residue was dissolved in CH₃ CN (50 ml) and a solution of AgNO₃in the remaining amount of CH₃ CN was added dropwise. The flask wassheltered from light.

After 8 hours the AgBr precipitate was filtered and the organic phasewas evaporated at reduced pressure.

The oily residue so obtained was dissolved in toluene (45 ml) and thesolution was filtered on a silica gel column (400 g). The eluate wasbrought to dryness at reduced pressure at 30° C. to give 20 g of3-nitroxymethylphenol.

Preparation of intermediate KETOPROFEN --COCl:

A chloride of 2-(3-benzoyl)phenyl propionic acid

KETOPROFEN 20 g

thionyl chloride 50 ml

were reacted and the solution was refluxed for 45 minutes. Thionylchloride was evaporated off at reduced pressure. An oily yellow residueweighing 21 g was obtained and used with no further purification.

Preparation of KETOPROFEN-Ar-NO₂

The reagents below were used in the following amounts:

KETOPROFEN --COCl 5.45 g

3-nitroxymethylphenol 3.9 g ##STR20## K₂ CO₃ 5.5 g AcOEt 50 ml:##STR21## K₂ CO₃ and AcOEt were added together; ketoprofen chloride wasthen added under nitrogen at t=0 in 30 minutes.

The whole was allowed to react for 5 hours at ambient temperature, thendiluted with H₂ O (50 ml). The organic phase was washed with 5% NaOH(2×10 ml) and evaporated off at reduced pressure. The resulting oilyresidue was chromatographed on silica using a toluol/EtOAc 9.5/0.5 v/vmixture as an eluant. The evaporation of the eluate gaveKETOPROFEN-Ar-NO₂ with a yield of 85%.

A ¹ H-NMR analysis (CDCl₃) (300 MHz) provided the following data: 1.63(3H,d); 4.00 (1H Q); 5.37 (2H,S); 7.01-7.89 (m,13H).

Mass spectrometry yielded a molecular weight value of 405.

Example 1d:

Preparation of compound A--X₁ --NO₂, herein referred to asIBUPROFEN-NO-DEG, wherein R belongs to group IV; X₁ is --(CH₂ --CH₂--O)₂ --, A=RCOO, R residue of IBUPROFEN, having formula:

    --(CH.sub.3).sub.2 CHCH.sub.2 C.sub.5 H.sub.4 --CH(CH.sub.3)--

The same procedure of example 1a was followed, using the above R,residue of IBUPROFEN, instead of residue R of group I as shown inexample 1a.

Example 1e:

Preparation of compound A--X₁ --NO₂, herein referred to asFLURBIPROFEN-NO-DEG, wherein R belongs to group III; X1 is --(CH₂ --CH₂--O)₂ --, A=RCOO, R_(3a) =H, R_(2a) =CH₃, R having formula: ##STR22##

The same procedure of example 1a was followed, using the above R,residue of FLURBIPROFEN, instead of residue R of group I as shown inexample 1a.

Example 1f:

Preparation of compound A--X₁ --NO₂, KETOROLAC-NO-DEG, wherein R belongsto group V; X₁ is --(CH₂ --CH₂ --O)₂ --; A=R, R of formula II, havingformula ##STR23##

The same procedure of example 1a was followed, using the above R,residue of KETOROLAC, instead of residue R of group I as shown inexample 1a.

Example 1g:

Preparation of compound A--X₁ --NO₂, TIAPROFENIC ACID NO DEG, wherein Rbelongs to group III; X₁ is --(CH₂ --CH₂ --O)₂ --, A=RCOO, R is theresidue of formula XXXV, wherein R is: ##STR24##

The same procedure of example 1a was followed, using the above R,residue of TIAPROFENIC ACID, instead of residue R of group I as shown inexample 1a.

Example 1h:

Preparation of compound A--X₁ --NO₂, NAPROXEN NO-DEG, wherein R belongsto group IV; X₁ is --(CH₂ --CH₂ --O)₂ --, A=RCOO, R is the residue offormula II of NAPROXEN, having the general formula ##STR25##

The same procedure of example 1a was followed, using the above R,residue of NAPROXEN, instead of residue R of group I as shown in example1a.

EXAMPLE 2 Pharmacological Examples

The products used above were pharmacologically characterised.

Example 2a: ASA-NO-DEG as prepared in example 1a;

Example 2b: DICLOFENAC-NO-DEG as prepared in example 1b;

Example 2c: KETOPROFEN-NO-DEG as prepared in example 1c;

Example 2d: IBUPROFEN-NO-DEG as prepared in example 1d;

Example 2e: FLURBIPROFEN-NO-DEG as prepared in example 1e;

Example 2f: KETOROLAC NO-DEG as prepared in example 1f;

Example 2g: TIAPROFENIC ACID NO-DEG as prepared in example 1g;

Example 2h: NAPROXEN NO-DEG as prepared in example 1h.

Toxicity

Acute toxicity was evaluated by orally administering a single dose of 1,3, 10, 30, 100 mg/Kg of produce groups of 10 mice.

The death rate and the occurence of toxic symptoms were reported over anobservation period of 14 days. Even after administration of a 100 mg/Kgdose the animals showed no sign of apparent toxicity.

Anti-inflammatory activity

Anti-inflammatory activity was determined by the carrageenin-oedemamethod as described by Winter et al. (Proc. Soc. Exp. Biol. Med. 111,544, 1962) in rats.

Analgesic activity

Analgesic activity was determined in Swiss mice as described byHendershot et al. (J. Pharmacol. Exp. Therap. 125, 237, 1959).

Tolerance

Gastric tolerance was measured by oral administration to rats assessingthe severity of the gastropathy induced in accordance with the criteriadescribed by Wallace et al. (Am. J. Physiol. 259, G642, 1990).

Platelet anti-aggregating activity

Platelet anti-aggregating activity was evaluated in vitro on humanplatelets stimulated by thrombin in accordance with the method describedby Bertele et al. (Science 220, 517, 1983).

Vasodilative activity

Vasodilative activity was determined in isolated rat aorta measuring theinhibition of the contraction induced by epinephrine in the tissueprepared in accordance with the method described by Reynolds et al. (J.Pharmacol. Exp. Therap. 252, 915, 1990).

COX Inhibition

The activity inhibiting cyclo-oxygenase was determined in isolatedcells. Endothelial cells of bovine aorta were used as a source of COX-1and macrophage line J774.2 as a source of COX-2. The same conditionsdescribed by Mitchell et al. (Proc. Nat. Acad. Sci. 90, 11693, 1993) forgrowth and the viability test were used.

In brief, the cells were incubated for 30 minutes with scalarconcentrations of the test product and the substrate (arachidonic acid)was then added and incubated for another 15 minutes. Enzyme activity wasdetermined radioimmunologically by measuring the formation of 6-keto-PGF1 alpha. In the case of cell lines J.774.2, the cells were incubated for12 hours with endotoxin to promote COX-2 formation.

Nitrosynthetase inhibition by LSP

The nitrosynthetase inhibition activity induced by lipopolysaccharide(LPS) was determined in rat neutrophils and stomach after administrationof one of the test compounds and compared with that obtained aftertreatment of the suspension vehicle only.

In brief, Wistar rats fasting for 24 hours before treatment were orallyadministered the test product (10 mg/Kg) and intravenously (caudal vein)administered LPS (5 mg/Kg).

Four hours later the animals were sacrificed and the blood--forneutrophils isolation--and the stomach taken.

Enzyme activity was determined in accordance with the method describedby Assreuy et al. (Br. J. Pharmacol. 108, 833, 1993).

Results:

The results obtained are described below.

As it may be observed from the data shown in tables 1 to 4, thepharmacodynamic activities (I and II in Table 1; Table 2) and thetolerance (Table 1 column III) of the nitroderivatives show a betterbalance as compared to natural products.

Table 4 also shows that, similarly to diclofenac nitroxybutylester, thediclofenac nitroderivative which is an object of this patent is capableof directly inhibiting cyclo-oxygenase COX-1 and COX-2, but with asignificantly lower variability.

TABLE 1 (Pharmacology col.I and II; Toxicology col.III)

Study of the anti-inflammatory (I) and analgesic (II) properties(pharmacodynamics) and gastrointestinal tolerance (III) (toxicity) ofthe test compounds after oral administration of doses ranging from 3 to30 mg/Kg in carboxymethylcellulose suspensions and constructingdose-response curves. The results shown are the potency ratio ascompared to the reference standard.

Activities are expressed as the potency ratio compared to the naturalproduct used as a unit standard. The nitroderivative is that of theshown examples, the natural reference compound is that shown as areference.

                  TABLE 1    ______________________________________    TEST COMPOUND  EXAMPLE   I        II  III    ______________________________________    NITRODERIVATIVE                   1a        1.2      1.1 0.2    ASPIRIN        reference 1.0      1.0 1.0    NITRODERIVATIVE                   1b        1.3      0.9 0.3    DICLOFENAC     reference 1.0      1.0 1.0    NITRODERIVATIVE                   1c        1.0      1.2 0.1    KETOPROFEN     reference 1.0      1.0 1.0    NITRODERIVATIVE                   1d        1.0      1.1 0.1    IBUPROFEN      reference 1.0      1.0 1.0    NITRODERIVATIVE                   1e        1.0      1.0 0.1    FLURBIPROFEN   reference 1.0      1.0 1.0    NITRODERIVATIVE                   1f        1.0      1.0 0.1    KETOROLAC      reference 1.0      1.0 1.0    NITRODERIVATIVE                   1g        0.9      1.3 0.1    TIAPROFENIC ACID                   reference 1.0      1.0 1.0    NITRODERIVATIVE                   1h        1.3      1.3 0.1    NAPROXEN       reference 1.0      1.0 1.0    ______________________________________

TABLE 2 (Pharmacodynamic activity)

Example of the anti-cyclooxygenase (I), platelet anti-aggregating (II)and vasodilative (III) properties of the test compounds tested in vitroat concentrations in the molar range from 10⁻⁵ to 10⁻⁷ of the product inwater/alcohol with the addition of small amounts of DMSO(dimethylsulphoxide). The activities are expressed as the potency ratioversus the natural product used as a unit standard, as stated in Table

                  TABLE 2    ______________________________________    TEST COMPOUND  EXAMPLE   I       II  III(°)    ______________________________________    NITRODERIVATIVE                   1a        1.5     3.0 60    ASPIRIN        reference 1.0     1.0 inactive    NITRODERIVATIVE                   1b        1.8     1.8 50    DICLOFENAC     reference 1.0     1.0 inactive    NITRODERIVATIVE                   1c        1.2     1.8 50    KETOPROFEN     reference 1.0     1.0 inactive    ______________________________________     (°) % of inhibitory action of the vasospasm induced by epinephrine

TABLE 3 (Biochemistry: Action on NOS for Septic Shock)

Study of the inhibitory properties of the nitrosynthetase (NOS) activityinduced by liposaccharide (LPS) in rats using oral doses ranging from 5to 20 mg/Kg suspended in a carboxymethylcellulose base.

                  TABLE 3    ______________________________________    NOS (°°)                                        NEUTRO-    TREATMENT       EXAMPLE   STOMACH   PHILS    ______________________________________    LPS             reference 100       100    LPS + NITRODERIVATIVE                    1c        40        30    KETOPROFEN of Ex.    LPS +           reference 35        55    NITROXYBUTYLKETOPRO-    FEN    LPS + NITRODERIVATIVE                    1b        40        52    DICLOFENAC of ex.    LPS + NITROXYBUTYLDI-                    reference 37        49    CLOFENAC    ______________________________________     (°°)inhibition relative to the group treated with LPS only.

TABLE 4 (COX-Inhibition Activity)

Study of the anti-cyclooxygenase (COX-1/COX-2) properties in isolatedcells.

Response expressed as a % of the controls with relative responsevariability.

                  TABLE 4    ______________________________________                           DOSE                           mg/ml                           (solu-                           tion                           of                  EX-      Table    COMPOUND      AMPLE    2)      COX-1  COX-2    ______________________________________    NITRODERIVATIVE                  1b       0.1     49 +/- 6                                          45 +/- 3    DICLOFENAC             1.0     29 +/- 4                                          22 +/- 4    DICLOFENAC    reference                           0.1     45 +/- 22                                          68 +/- 11    NITROXYBUTYLESTER      1.0     24 +/- 10                                          41 +/- 11    NITRODERIVATIVE                  1e       0.1     51 +/- 5                                          47 +/- 4    FLURBIPROFEN           1.0     22 +/- 3                                          18 +/- 2    FLURBIPROFEN  reference                           0.1     48 +/- 18                                          46 +/- 23    NITROXYBUTYLESTER      1.0     29 +/- 13                                          22 +/- 14    ______________________________________

We claim:
 1. A compound having the formula:

    A--X.sub.1 --NO.sub.2

or their salts, wherein: A=R(COX_(u))_(t), wherein t=0 or 1; u=0 or 1,X=O, NH, NR_(1C), wherein R_(1C) is a linear or branched alkyl having 1to 10 C atoms; R is selected from the following groups: group I),wherein t=1 and u=1, and R is: ##STR26## wherein: R₁ is an OCOR₃ group;R₃ is methyl, ethyl or a linear or branched C₃ -C₅ alkyl, or anonaromatic or aromatic heterocycle with a single ring having 5 or 6atoms containing one or more heteroatoms independently selected from O,N, and S; R₂ is hydrogen, hydroxy, a halogen, a linear or branched alkylhaving 1 to 4 C atoms, a linear or branched alkoxyl having 1 to 4 Catoms, a linear or branched perfluoroalkyl having 1 to 4 C atoms, nitro,amino, mono- or di-(C₁₋₄) alkylamino; or R₁ and R₂ together are adioxymethylene group, with the proviso that when X=NH, then X₁ isethylene and R₂ =H; R₁ cannot be OCOR₃ in position 2 when R₃ is methyl;nI is 0 or 1; group II) wherein t=1 and u=1, and R is: ##STR27##wherein: R_(II5) is H, a linear or branched C₁ -C₃ alkyl; R_(II6) is H,a linear or branched C₁ -C₃ alkyl; or, when R_(II5) is H, R_(II6) isbenzyl; R_(II1), R_(II2) and R_(II3), independently from one another,are H, a linear or branched C₁ -C₆ alkyl or C₁ -C₆ alkoxy, or Cl, F, Br;R_(II4) is R_(II1) or Br; group III), wherein t=1, u=1 and R is:##STR28## wherein: R_(2a) and R_(3a) are H, a linear or branched,substituted or nonsubstituted C₁ -C₁₂ alkyl, allyl, with the provisothat when one of the two groups is allyl, the other is H; R_(1a) ischosen from ##STR29## or group IIID, wherein R_(1a) is: ##STR30##wherein in formula (IV), R_(III1) is H or SR_(III3), wherein R_(III3)has from 1 to 4 C atoms, linear or branched; R_(III2) is H orhydroxy;wherein in formula (XXI), R_(XXio) is H, a linear or branchedalkyl having from 1 to 6 C atoms, a C₁ -C₆ alkoxycarbonyl bound to a C₁-C₆ alkyl, a C₁ -C₆ carboxylalkyl, a C₁ -C₆ alkanoyl, unsubstituted orsubstituted with a halogen, benzyl or halobenzyl, benzoyl orhalobenzoyl; R_(XXi) is H, a halogen, hydroxy, CN, a C₁ -C₆ alkyl, a C₁-C₆ alkoxy, acetyl, benzyloxy, SR_(XXi2), wherein R_(XXi2) is an alkylC₁ -C₆ ; a perfluoroalkyl having from 1 to 3 C atoms, a C₁ -C₆carboxyalkyl, NO₂, amino, sulphamoyl, a dialkyl sulphamoyl with thealkyl having from 1 to 6 C atoms, or a di-fluroalkyl sulphonyl with thealkyl having from 1 to 3 C atoms; R_(XXi1) is a halogen, CN, a C₁ -C₆alkyl, a C₁ -C₆ alkoxy, acetyl, acetamide, benzyloxy, SR_(III3) is asabove defined, a perfluoroalkyl having from 1 to 3 C atoms, hydroxy, acarboxyalkyl having from 1 to 6 C atoms, NO₂, amino, a mono- ordi-alkylamino having from 1 to 6 C atoms, sulphamoyl, a di-alkylsulphamoyl having from 1 to 6 C atoms, or a di-fluoroalkyl sulphamoylhaving from 1 to 6 atoms; or R_(XX1) together with R_(XXi1) is analkylene dioxy having from 1 to 6 C atoms;wherein in formula (XXXV), Aris phenyl, a hydroxyphenyl unsubstituted or substituted with a halogen,an alkanoyl and an alkoxy having from 1 to 6 C atoms, a trialalkylhaving from 1 to 6 C atoms, cyclo-pentyl, cylo-hexyl, cyclo-heptyl,heteroaryl, furyl, pyridyl; group IV) wherein t=1, u=1, and R is##STR31## wherein: R_(IVd) and R_(IVd1) are at least one H and the othera linear or branched C₁ -C₆ alkyl, or a di-fluoroalkyl with the alkylhaving from 1 to 6 C, or R_(IVd) and R_(IVd1) together form a methylenegroup;wherein R_(IV) is selected from: ##STR32## wherein in formula(II): R_(v-ii) is a 1-6 C alkyl, a cycloalkyl having from 3 to 7 Catoms, an alkoxymethyl having from 1 to 7 C atoms, a trifluroalkylhaving from 1 to 3 C atoms, vinyl, ethinyl, halogen, an alkoxy havingfrom 1 to 6 C atoms, a di-fluoroalkoxy with the alkyl having from 1 to 7C atoms, an alkoxymethyloxy having from 1 to 7 C atoms, analkylthiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylmethylthio with the alkyl having from 1 to 7 C atoms, cyano,di-fluoromethylthio, phenyl or phenylalkyl substituted with the alkylhaving from 1 to 8 C atoms; wherein in formula (III): R_(iv-iii) is alinear or branched C₂ -C₅ alkyl, a C₂ and C₃ alkyloxy, allyloxy,phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C atoms; group V),R is: ##STR33## wherein in the radicals of formula (II), R_(vii) is H ora linear or branched alkyl having from 1 to 4 C atoms; R_(vii-1) is asdefined for R_(vii) or a linear or branched alkoxy having from 1 to 4 Catoms; Cl, F, Br; and the position of R_(vii-1) is o-, m- or p-;X₁ inthe formula A--X₁ --NO₂ is a bivalent connecting bridge selected fromthe following: --YO-- wherein Y is:a linear or branched C₁ -C₂₀alkylene, with the proviso that the connection bridge is excluded when Ris:a radical of group I) except radicals of formula (Ib) and (Ic); aradical of group II) except radicals of formula (II_(b)); a radical ofgroup III) except radicals of group (IIID); a radical of group IV); aradical of group V), except radicals of formula (X) and including--(CH₂)₄ -- for the compounds of formula (III) and (IV);or acycloalkylene having from 5 to 7 carbon atoms, excluding this connectingbridge when R is a radical of formula (Ia) of group I; ##STR34## whereinn₃ is 0 or an integer from 1 to 3, ##STR35## wherein nf' is an integerfrom 1 to 6, ##STR36## wherein R_(1f) =H, --CH₃ and nf is an integerfrom 1 to
 6. 2. The compound according to claim 1, wherein,in group I):in the radicals of formula (Ia): X is O, R1 is acetoxy, X₁ is (CH₂ --CH₂--O)₂, R₂ is hydrogen; in the radicals of formula (Ib): R₃ =CH₃, nI=O, Xis equal to O, X₁ is ethylene;in group II): wherein R_(II1), R_(II2) andR_(II4) are H, R_(II3) is chlorine and R_(II3) is in the ortho positionrelative to HN; R_(II5) and R_(II6) are H; X is equal to O, and X₁ is(CH₂ --CH₂ --O)₂.
 3. A pharmaceutical composition containing thecompound according to claim 1 or 2 in admixture with a pharmaceuticallyacceptable excipient.
 4. A method for the treatment of septic shockwhich comprises administration of an effective amount of the compoundhaving the formula:

    A--X.sub.1 --NO.sub.2

wherein A is as defined by claim 1 or 2 and X₁ is a bivalent connectingbridge chosen from the following: --YO--wherein Y is: a linear orbranched C₁ -C₂₀ alkylene, an unsubstituted or substituted cycloalkylenehaving from 5 to 7 carbon atoms; ##STR37## wherein n₂ is 0 or an integerfrom 1 to 3, ##STR38## wherein nf' is an integer from 1 to 6, ##STR39##wherein R_(1f) =H, --CH₃ and nf is an integer from 1 to
 6. 5. A methodfor the treatment of inflammation which comprises administration of ananti-inflammatory amount of a compound having general formula:

    A--X.sub.1 --NO.sub.2

wherein A is defined by claim 1 or 2 and X₁ is a bivalent connectingbridge chosen from the following: --YO--where Y is: a linear or branchedC₁ -C₂₀ alkylene, excluding this connecting bridge when R is:a radicalof group II) except radicals of formula (II_(b)); a radical of groupIII) except radicals of group (IIID) a radical of group IV); a radicalof group V), except radicals of formula (X) and including --(CH₂)₄ --for the radicals of formulae (III) and (IV); an unsubstituted orsubstituted cycloalklene having from 5 to 7 carbon atoms; ##STR40##wherein n₃ is 0 or an integer from 1 to 3, ##STR41## wherein nf' is aninteger from 1 to 6, ##STR42## wherein R_(1f) =H, --CH₃ and nf is aninteger from 1 to
 6. 6. A method for anti-thrombotic treatment whichcomprises administration of an antithrombotic amount of a compoundhaving the formula

    A--X.sub.1 --NO.sub.2

wherein A is as defined by claim 1 or 2 and X₁ is a bivalent connectingbridge selected from the following: --YO--where Y is: a linear orbranched C₁ -C₂₀ alkylene, excluding this connecting bridge when R is:aradical of group II) except radicals of formula (II_(b)); a radical ofgroup III) except radicals of group (IIID) a radical of group IV); aradical group of V), except formula (X) and including --(CH₂)₄ -- forthe radicals of formulae (iii) and (IV); a cycloalkylene having from 5to 7 carbon atoms, ##STR43## wherein n₃ is 0 or an integer from 1 to 3,##STR44## wherein nf' is an integer from 1 to 6, ##STR45## whereinR_(1f) =H, --CH₃ and nf is an integer from 1 to
 6. 7. A method foranalgesic treatment comprising administration of an analgesic amount ofa compound of the general formula:

    A--X.sub.1 --NO.sub.2

wherein A is as defined by claim 1 or 2 and X₁ is a bivalent connectingbridge selected from the following: --YO--where Y is: a linear orbranched C₁ -C₂₀ alkylene, excluding this connecting bridge when R is:aradical of group II) except radicals of formula (II_(b)); a radical ofgroup III) except radicals of group (IIID); a radical of group IV); aradical group of V), except formula (X) and including --(CH₂)₄ -- forthe radicals of formulae (iii) and (IV); an unsubstituted or substitutedcycloalkylene having from 5 to 7 carbon atoms; ##STR46## wherein n₃ is 0or an integer from 1 to 3, ##STR47## wherein nf' is an integer from 1 to6, ##STR48## wherein R_(1f) =H, --CH₃ and nf is an integer from 1 to 6.8. The compound of claim 1, wherein R is as defined by group III,formula (IV), wherein R_(III1) and R_(III2) are H, R_(3a) is H, R_(2a)is methyl, and X=O.
 9. The compound of claim 1, wherein R is as definedby group III, formula (XXI), wherein R_(XXio) is H, the connectingbridge is in position 2, R_(XX1) is H, R_(XX11) is chlorine and is inthe para position relative to nitrogen; R_(3a) is H, R_(2a) is methyl,and X is O.
 10. The compound of claim 1, wherein R is as defined bygroup III, formula (XXXV), wherein Ar is phenyl, R_(3a) is H, R_(2a) ismethyl, and X is O.
 11. The compound of claim 1, wherein R is as definedby group III, formula (II), wherein R_(3a) is H, R_(2a) is methyl, andX=O.
 12. The compound of claim 1, wherein R is as defined by group III,formula (VI), wherein R_(2a) is CH₃.
 13. The compound of claim 2,wherein R is as defined by group III, formula (VI), wherein R_(2a) is H,R_(3a) =CH₃, and X=O.
 14. The compound of claim 1, wherein R is asdefined by group III, formula (VIII), wherein R_(2a) =R_(3a) =H and X=O.15. The compound of claim 1, wherein R is as defined by group III,formula (VII), wherein R_(3a) =X, R_(2a) =--CH₃ and X=O.
 16. Thecompound of claim 1, wherein R is as defined by group III, formula(III), wherein R_(2a) =R_(3a) =H and X=O.
 17. The compound of claim 1,wherein R is as defined by group III, formula (IX), wherein R_(3a) is H,R_(2a) is --CH₃ and X=O.
 18. The compound of claim 1, wherein R is asdefined by group III, formula (X), wherein R_(2a) =R_(3a) =H and X=O.19. The compound of claim 1, wherein R is as defined by group III, andR_(1a) is defined by group IIID, formula (IIIa), wherein R_(2a) =H,R_(3a) =--CH₃, u=1 and X=O.
 20. The compound of claim 1, wherein R is asdefined by group III, and R_(1a) is defined by group IIID, formula(XXX), wherein R_(2a) =H, R_(3a) =CH₃, u=1 and X=O.
 21. The compound ofclaim 1, wherein R is as defined by group III, and R_(1a) is defined bygroup IIID, formula (XXXI) wherein R_(2a) =H, R_(3a) =CH₃, u=1 and X=O.22. The compound of claim 1, wherein R is as defined by group III, andR_(1a) is defined by group IIID, formula (XXXII) wherein R_(2a) =R_(3a)=H, u=1 and X=O.
 23. The compound of claim 1, wherein R is as defined bygroup III, and R_(1a) is defined by group IIID, formula (XXXIII) whereinR_(2a) =R_(3a) =H, u=1 and X=O.
 24. The compound of claim 1, wherein Ris as defined by group III, and R_(1a) is defined by group IIID, formula(XXXVI) wherein R_(2a) =H, R_(3a) =CH₃, u=1 and X=O.
 25. The compound ofclaim 1, wherein R is as defined by group III, and R_(1a) is defined bygroup IIID, formula (XXXVII) wherein R_(2a) =R_(3a) =H, t=1 and X=O. 26.The compound of claim 1, wherein R is as defined by group IV, formula(II) wherein R_(iv-ii) is CH₃ O, R_(ivd) is H and R_(ivd1) is --CH3,X=NH or O and X₁ =--(CH₂ --CH₂ --O)₂.
 27. The compound of claim 1,wherein R is as defined by group IV, formula (X) wherein R_(IVd) is Hand R_(IVd1) is --CH₃, X=NH or O and X₁ is equal to (CH₂ --CH₂ --O)₂.28. The compound of claim 1, wherein R is as defined by group IV, formal(III), wherein R_(IV-111) is ##STR49## and R_(IVd) =H, R_(IVd1) is--CH₃, X=NH or O and X₁ is equal to (CH₂ --CH₂ --O)₂.
 29. The compoundof claim 1, wherein R is as defined by group V, formula (II), whereinR_(vii) and R_(vii-1) are H, and A=R and t=0.
 30. The compound of claim1, wherein R is as defined by group V, formula (V), wherein A=R and t=0.31. The compound of claim 1, wherein R is as defined by group V, formula(VII), wherein A is RCO and t=1 and u=0 or A is R and t=0.
 32. Thecompound of claim 1, wherein R is as defined by group V, formula (IX),wherein A=R and t=0.
 33. The compound of claim 1, wherein R is asdefined by group V, formula (IX), wherein A=RCO, t=1 and u=0.
 34. Thecompound of claim 1, wherein R is as defined by group V, formula (III)wherein A=RCOO, t=1 and u=0 or 1; or A=R and t=0.
 35. The compound ofclaim 1, wherein R is as defined by group V, formula (III) wherein A=Rand t=0.
 36. The compound of claim 1, wherein R is as defined by groupV, formula (IV), wherein A=RCOO, t=1, and u=1.
 37. The compound of claim1, wherein R is as defined by group V, formula (X), wherein t=0.
 38. Thecompound of claim 1, wherein R is as defined by group V, formula (XI),wherein u=1, X=O; and t=0.
 39. The compound of claim 1, wherein R is asdefined by group V, formula (XII), wherein R_(2a) =R_(3a) =H, u=1, X=O,and t=0.
 40. The compound of claim 1, wherein R is as defined by groupV, formula (XIII) t=0.